Aberrations of function or metabolism of the putative amino acid (AA) neurotransmitters, glutamate (GLU) and GABA, have been inplicated in the etiology or sequelae of several neural disorders, e.g., Huntington's chorea, Parkinson's Disease, epilepsy and certain forms of olivopontocerebellar atrophy. In addition, a GLU-analog, the excitotoxin kainic acid (KA), when injected directly into rat neostriatum causes neuronal death with biochemical alterations similar to those observed in Huntington's chorea, raising the intriguing possibility that endogenous excitotoxins may be involved in such disorders. Previous studies by the applicant have shown that an alteration in energy metabolism and the normal neuronal-glial metabolism of GLU may play a role in the neurotoxicity of KA. This proposal will continue studies on the mechanism of toxicity of excitatory AA as well as initiate experiments to test hypotheses concerning the disparate distribution of transmitter AA metabolism between neurons and glia. The metabolism of GLU, aspartate, glutamine and GABA, will be studied in vivo and in vitro in neostriatal preparations from normal and cortically-ablated rats; in the latter animals KA has far less potency as a neurotoxin. Data will be evaluated in terms of relative contributions of neuronal and glial structures in the lesioned animals and scrutinized for clues as to why KA is not toxic. AA and energy metabolism, and the effect thereon, of excitotoxic AA will also be examined in cerebellar slices from rats of various ages and correlations made with stimulation of cyclic nucleotide production. To test whether glutamine is a major precursor of transmitter GLU and GABA, cerebellar and neostriatal slices will be incubated with various radioactive precursors in the presence of a glutaminase inhibitor. The labelling of veratridine-releasable AA (i.e., transmitter pools) will be examined in these studies. Using inhibitors of cytoplasmic aspartate aminotransferase and mitochondrial GLU translocases, intracellular metabolism of transmitter GLU synthesis in tissue slices and synaptosomes will be studied. Hopefully, this proposal will lead to novel ways of studying regulation of transmitter AA metabolism in normal and diseased states.